Edward was born in sanctuary within Westminster Abbey on November 4, 1470, while his mother was taking refuge from the Lancastrians who dominated the kingdom while his father, the Yorkist King Edward IV of England, was out of power. He was created Prince of Wales in June, 1471, following his father's restoration to the throne, and appeared with his parents on state occasions. (For a brief period after his birth and before he was officially given the title, he was one of two living Princes of Wales, the other being the only son of Henry VI of England, who was killed in May, 1471.)

Edward IV, having established a Council of Wales and the Marches[?], duly sent his son to Ludlow Castle to be its nominal president. It was at Ludlow that the prince was staying when news came of his father's sudden death.
Edward inherited the throne on April 9, 1483, at the age of twelve. His father's brother Richard, Duke of Gloucester, was entrusted with the role of protector to his young nephews, Edward V and Richard, Duke of York. He intercepted Edward's entourage on its return journey from Wales and escorted the princes to London. Less than three months later, Richard took the throne himself. On June 25, Parliament declared his nephews illegitimate after a priest (believed to be the Bishop of Bath and Wells) presented evidence that Edward had contracted to marry Lady Eleanor Talbot before he married Elizabeth Woodville; this would have made his marriage to Elizabeth invalid. Richard's other brothers, Edmund and George, Duke of Clarence, had both died before Edward, leaving Richard next in line for the throne.

Once the two boys went into the Tower of London, they were never seen in public again. What happened to them is one of the great mysteries of history, and many books have been written on the subject. It is generally believed that they were killed, and the usual suspects are: their uncle, King Richard; Henry Stafford Duke of Buckingham; and Henry Tudor, who defeated Richard and took the throne as Henry VII.

After the princes' disappearance, there was much uncertainty as to their fate. If they were killed, the secret was well kept; conversely, there was no evidence of their survival or of their having been shipped out of the country. When a pretender, Perkin Warbeck, turned up claiming to be Prince Richard, in 1495, William Stanley (younger brother of King Henry's stepfather, Thomas Stanley, 1st Earl of Derby), who, despite his Yorkist[?] sympathies, had turned against Richard III at the Battle of Bosworth Field and helped King Henry win it, said that, if the young man was really the prince, he would not fight against him, thus demonstrating that some Yorkists had not given up hope of the princes being still alive.

In 1674, some workmen remodelling the Tower of London dug up a box containing two small human skeletons. They threw them on a rubbish heap, but some days or weeks later someone decided they might be the bones of the two princes, so they gathered them up and put some of them in an urn that Charles II of England ordered interred in Westminster Abbey. In 1933 the bones were taken out and examined and then replaced in the urn in the vault under the Abbey. The experts who examined them could not agree on what age the children would have been when they died or even whether they were boys or girls. (One skeleton was larger than the other, and many of the bones were missing, including part of the smaller jawbone and all of the teeth from the larger one.)